AU7711081A - Dihydropyridines linked in the c-3 position - Google Patents

Abstract

1. 1,4-Dihydropyridines which are linked in the C-3 position, of the general formula I see diagramm : EP0052300,P19,F4 in which R and R' are identical or different and each represent a phenyl radical or a thienyl, furyl, or pyridyl radical, the phenyl radical is optionally substituted by one or two identical or different substituents from the group comprising nitro, cyano, azido, halogen, trifluoromethyl, hydroxyl, amino, alkyl, alkoxy, alkylamino or alkylmercapto, with in each case 1 or 2 carbon atoms in the alkyl groups, R**1 and R**1' are identical or different and each represent a straight-chain or branched hydrocarbon radical having up to 6 carbon atoms which is optionally interrupted in the chain by an oxygen atom and which is optionally substituted by fluorine, chlorine, hydroxyl, phenyl or phenoxy, R**2 , R**2' , R**4 and R**4' are identical or different and each represent hydrogen or a straight-chain or branched alkyl radical which has up to 4 carbon atoms and which is optionally substituted by fluorine, chlorine, hydroxyl, phenyl or amino, R**3 and R**3' are identical or different and each represent hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, benzyl or phenethyl, optionally substituted by hydroxyl, fluorine or chlorine, Y and Y' are in each case identical or different and each denote - COO -, - CONH -, - CO - or - SO2 - and X denotes a bridge member which consists of one to ten CH2 groups as the chain member, and none of these CH2 groups are allowed as a ring member, it being possible for this bridge member additionally to contain, in any sequence, 1 to 3 identical or different chain members from the group comprising O, S, CO, CS, NR**5 , C(R**6 )2 , CH = N, phenylene, naphthylene, pyrrylene, cycloalkylene with 5 to 7 carbon atoms, piperazinylene, piperidinylene, pyrrolidinylene or morpholinylene, wherein R**5 represents hydrogen, benzyl or alkyl having 1 to 4 carbon atoms and R**6 represents hydrogen, benzyl, phenyl, fluorine, chlorine, alkyl having 1 to 4 carbon atoms, hydroxyl, trifluoromethyl, cyano, carboxyl or amino and their pharmacologically acceptable acid addition salts.

Description

oaaxkd q~PUP q-P 4U aJJTP 1'.iO TU@IPT pu PUPe (ao T 'Q sT qolt BT) TRX~TP-' OS PUPOp~wuIuoqdTns OPTui~oqT oji GJT p 'RXO)TT~qaPO 'TSX0qaxsO 'OPTIzP'OUPRO "oa~q u couTmPTSeTR, e OUTUIP CT~xOaPSLT I XOTOOpJk'od

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1 0 PATENT APPLICATION FORM (CONVENTION 'ND NON-CONVENTION)

COMMONWEALTH, OF AUSTRALIA Regulation 9

PatentsAct 195s

APPLICA4-rtN FOR A STANDPAI PA%>ENT OR A STANDARD PATENT OF AJDD);TION

Intert full name of ~vea) BAYER AXTIENGESELLS CHA FT

(b)I nae~ F"-Ll add fresa of app'o ntls

Deleteas hereby apply for the grant of a Standard Patent fran invention entitled NEW..4 appropriate

DIHYDROPYRIDINE COMPOUNDS LINKED IN THE C-3 PO-SITIO ,HEIR mart title of Invention P.RODUCTIN AND q!HE IR ffD NAL USE" which is described in the accomp3anying (cP 49)specfication. For a Convention application details of basic application(s)

NUMBER COUNTRY DATE OF APPLICATION for Co-ventlon catas onlj'

42 769.1 GERMANY November 13, 1980

For Patents of Addition only. For

I/We request that the Patent may be granted as a Patent of Additioq (1I Insert number 'arent/main' (g) epplltetj~n/or 'fnr4nn Ann No patent ,,to l~ Ah appropiate PA~TPATENT OFFICE Insert fleme o par n smarn ppealnor patent asap- proprIata.

Insert da8y, month and -)OAR'-0C t 1 ylear form day 198 Islined. FEE STAMP VO VALUE: 0P

o ppllant ig uf or Auirml an atorney. L OW-mn aTki Q)l MAPLOFFICER

(kt)Seal,It any. N V(k) BAYER AKTI1-ENGESELLS CHAFT (clignat-ure

By its Patent--Atto,rney§ ~To: ARTHUR S. CAVE &1/0. Sydney

Cornmissionqg of Patents

I'.'l

Dsimie I1

K~ E3. t0]

1 0it I ~iiI I,1

kiI1I

~IN 21' 0 .4s

COMMONWEALTH OF AUSTRALIA Form Regulation PATENTS ACT, 1952 13(2)

COMPLETE SPECIF'CATION' (ORIGINAL)

2 .(L 0, C) .0 2~ .0~

1) 2AU 0, AUA/7 1 0 8

(54) DIHY,'DROPYRIDINE5 LINKED IN- THE C-3 <POSITION C) (71) BAYER A.G, 77 110Y("8 1 (22) 5 11. 81 (31) 3:04 2769 (32 11 .80 (33) DE 0 (43) 2 0 5. 82 2. (51,)3 CO7'P3 In, /1A4- C07D 405/14 CD7D 409/14 C07D 4J13/14 C07D 417/14 C 71 211/90 1 (72) Gold ma nnr, Dr. ,Van&Knorr, A. '-Dr. (74) CN (57) Compounds useful in combati ng c~rculatory illnesses. r Claim domnpounds which are l,LI-dihydropyridines which ar'e linked in the C-3 pozition, of the general formula

.R100oc COOR I

or, a salt thereof, 0 ,in which Ra,-nd RFi are identical or diffeZ'"ent and each represents an aryl r,..adical or a -heterocyclic 0 radical selec 1 thienyl, furyl, P'rrryl, pyrazolyl, imidaz'lyl,, oxazolyl, isoxazolyl, -thiazolyl, pyridyl, pyridazinyl,7pyr-imidyl, pyraziiyl, quinolyl, isoquinolyl, indolyl,,benzimidazolyl;' quinazolyl and Qulnoxalyl, thea .4lradicalor the heterocyclic ,radical A optionally containing.l to 3,identical different subs tituents selected from phenyl, alkyl',\akn alkoxy, atk-enoxy, alkylene, dioxyalky]Lene,, la Ie n, jmonofluoroalky,, polyrfJ-ioroalkyl, monoflubi &alr',i-v V 2~

00 1 V~ ND, 02 TI 6 ~o022.

0 y j~A.~2~vr0

-'~V2o

(1)AU-iA1-7 ~>0/81 -2 1 polyffL6oroalkoxy, hydroxyl, amino, alkylamino, ni~fo,, cyano, azido, carboxyl,, carbalkoxy, (carboxamido, suiphonarnido "and SO -al~kyl (ihi which is 0, 1 or 2), 1 R and R are identical pr dif ferent, and each r-,epresen -t ight-chain, branched or cy-lc saturated or unsaturated hydrocarb(T-! adical C which is onpiUonally interrupted in the chain by 4 and which is optionally kub I or- 2 oxyge~n a'toa, siituted by halog:n or hyad cpyl, or by a hn\I phenoxy phe-nylt1.io or pheny~j'-sulpoy group, hh Sin t u /is opinlysubstit'Oted by I1i,.logen, cyano, didlky'.arnino, allkoxy, alkyl, triflutri,methyl or nitro;' II 2, R R and R are identical, or di-ff ere n, and _eaci 17 repr'esent 4 hyVdl-rogen atom or a',straight-' chain, branched or cycl-ic, saturated or u~lnsaturated hyd1 rod< bon i/'adical'wlI-Ich is optionally sp~bstitut( d by jbalogen, h y oxy 1, aryl ~or amino, or repi1eqent -an amino group, v4"ich in tu4gn is opt iona-11-i sub- St.tte bybaa 1 and th i hydroW) carbon iradical can be S r~ightc ha~n, branch4,d or cyclic and satu at or unsaturate) and is in turn bnti l i substiztuted, Haxid R3 a,e\ identical or different a d acf~f ~rep~en a ydrgenat om or an optionally subst~t- ate~d--stra:igh:-cbaain or bi-anched alkyjl radio 1 whi. ,h ;jio'aI~ interrupted in',thea~v~ chain by on -~or tW o, o xygen atoms, or represent an optionally Substitut2ed aryl oraralkyl radical, Y "an~dV a 00~in each case identical or diffe-rent and ach denote 0 0f II 0

or' -S and ~Xrp'esikn'ts i~ a bridge member 'with at least one CH2 -group and at most 9 ad~p.jcernt CH gr~s, 04 l

eig ossbl fx, ,hs rille membeiP additionally 'to cbntain, a seirc Sy' e 0~5,ietclo -dentical o

PATENT AND TRADE- C'RK ATroANE J S IIy, F A. S YVNEY

A.S.C,

-3 (11) AU-A.1-77 110/81 different ahzin.mlnbers selected from 0, S, So, SO2V CO, CS, NR )2GR6 C6 CH=N, arylene, heteroarylene, cycloalkylene, cyclo- alkenylene,"piperazinylene, pi-peridinylene, A pyrrolidinylene and morpholihylefle, wherein R 5 represents a hydrogen.atom or an alkyl or aralk~yl radical and R 6 represents a hydrogen atom or ap. aralkyl, aryl, heteroaryl, alkyl, alkenyl, alkin~rl,\alkoxy, al.kenoxy, alkinoxy, alkylene, dioxyalkylene, lklogen, mono- fluoroalkyl, poly fluoroal~yl1, monof~uoroalkoxy, polyfluoroalkoxy, hydroxyl, amnino, alkylamino, nitro, cyano, _'azido, carboxyl, carbalkoxy, car- boxamido, sulphonamido or SOM-alkyl (in which m is 0$ 1 or 2) radical, in which the actxyl, alkyl. and heteroaryl radical can ir,turn be substituted by one to thr~e identical or different radicals selected from aryl, alkyl, alkoxy, aralkyJidioxy alkylene, halogen, monofluoroalkyl, polyfluoro- alkyl, m~nofluoroalkoxy, polyfluoroalkox-Y, hydroxyl, amino, alR.Vlamino, npit ro, cyano, azido, carboxyl, carbalko'xy, carboxamido,_ sulphonarnido and SO-m alky, (in which m is 1-or 2)

J)'

!I 0"]

COMMONWEALTH OF AUSTRALIA Form

1952 Regulation PATENTS ACT, 13(2) Thle COMPLETE SPECIF CATION dim~eric 1,4 (ORIGINAL) one ancther FOR OFFICE USE their prepar, an influence Short Title: It Int. Cl: pyridine den N

properties (E 58, 578 (1971 Application Nuknber: Lodgbd: Accc i compounds whi Complete Specification-Lodged: C-3 position, Accepted: 1apsed: Published,

Priority:

or a salt tlc Related A-'t: in whichi K an repr rpdi IQ BE COMPLETED BY APPLICANT 20 f pyra Name of Applicant: BAYER AKTIENbESELLSCHAFT ,-thia, PYra2 indol Address of ApplicariO Leverkusen, Bayerwerk, Germany qu i r radi. Actual Inventor: Siegfried Goldmann, Dr. Andreas Knorr.

alky2 Address for Service: A #THUR S. CAVE CO., Patent and Trade Mark dioxy At torneys, I Alfred Street, Sydney, New So~th Wales, Australia, 2000. polyf alk'ox Complete Specifircation fo% the invention entited: New l,4-dihydOpy- r'idine compou"13- linked f ie C-3 position, their production a d Le A 20 633 their medicinal use" The following statement'is 'a full description of this invention, including the best method o f-performing it known to me:-

III i ASC-49

used in this Specification means phyIsically discrete so constitute coherent units suitable for medical administration each only or prefe containing a daily dose or a multiple (up to four times)

IlA- Type lb (Pha) azid The present inv r6tion relates to certain new am i d dimeric 1, 4 di~ydr opyri dine conripounds which are linked to one another in the> -position, to several processes for rep x their preparation, and to their use in medicaments haviriF7 s atL an influence on the circulation. whi c It is already known that certain l,L-dihyd.,'o- 1 OT pyridine derivatives have interesting pharmacological subc, properties (see F. Bossert et al., Naturwisserischaften p her 58, 578 (1971) and DT-OS (German Published Specification) wh i C 102,7,7) c yar Accordtng to the present invention we provide compounds which are l,4-dihydropyridines linked in the C-3 position, of the genieralI formula, anid

R 1 0c. COOR 1 (IT) an R'3' subc or a salt tiicreof, hydi in which or( R and RI are identical or different and each t ur i represents an aryl radical or a heterocyclic R3 rpdical selected from thienyl, furyl, pyrryl, rep pyrazolyl, imridazolyl, oxazolyl, isoxazolyl, sub., ,-thiazolyl, pyridyl, pyridazinyl, pyrimidyl, SwhL pyrazinyl, quiliol yl, isoquiinolyl, by indo~yl, benzimidazolyl, quinazolyl and opt: quir -Oxalyl, the aryl radical or the heterocyclic Y a radical optionally containing 1 to 3 identicalor and di-..ferent substituents selected from phenyl, 0 -C-I alkyl, alkenyl, alkoxy., alkenoxy, alkylene, dioxyalkylene, halogen, monofluoroalkyl, X. polyfluoroalkyl, inonofluoroalkoxy, polyfluoro- r, alkoxy, hydroxyl,. Amino, alkylamino, nitro, qyano, be i: Le A 20 63 Le A 20 638

so constituted that they release the active ingredient glycol, dixpeti' only or preferably in a particular part of' the intestinal azido, carboxyl, carbalkoxy, carboxamido, sulphon- to amido and SO -alkyl (in which m is 0, 1 or 2), H and R are identical or different and each O, represent a straight-chain, branched or cyclic, CsC saturated or unsaturated hydrocarbon radical interrupted in the chain by 5 cyc which is optionally pyr 1 or 2 oxygen atoms and which is optionally wherein substituted by halogen or hydroxyl, or by a phenyl, phernoxy, phenylthio or ph nylsulphonyl group, ara which in turn is optionally substituted by halogen, R6 cyano, dialkylamino, alkoxy, alkyl, trifluoro- heti methyl or nitro, 2 2 41 alk R2 R, R' and R are identical or different 0i hal and each represent a hydrogen at6ir or a straight- flu' chain, branched or cyclic, saturated or unsaturated 15 alk: hyrocarbon radical which is optionally substituted oxy by halogen, hydroxyl, aryl or amino, or represent whi, an amino group, which in turn is optionally alk substituted by a hydrocarbon radical, and this sub hydrocarbon radical can be straight-chain, branched 20 rad: or cyclic and saturated or unsaturated and is in dio: turn optionally substituted, alk; R3 and R3 are identical or differt and each amii represent a hydr6gen atom or an optionally carl substituted straight-chain or branched alkyl radical 25 (in which is optionally interrupted in the alkyl chain Acce by one or two oxygen atoms, or represent an provide a optionally substituted aryl or aralkyl radical, invention, Y and,,Y' are in each case identical or different a) a hydrt and each denote formula 0 0 0 0 i t It or -SO 2 and X represents a bridge member with at least one CH 2 group and at most 9 adjacent CH2 groups, it being possible for this bridge member additionally

Le A 20 638 Le A 20 631

16 medical admini glycol, dimethylformamide, oils (for example ground 4- N V, A e,,Pt"l -Pnrfrtslf II r I I n I ei n ri I nnr i- of the followi to-contain. in anfy sequence, I to identical rdifferent chairn members seleqted from in whicl-, K03 S so, OCO, ,CS, NR5 C(1R6 6R CR 6 R, CEC, CH=N, arylene, heteroarylene, cycloalkylene, cycloalkenylene, piperazinylene, piperidinylene, is reacte pyrrolidinylene and morpholinylene, 5 3-carboxy where in represents a hyd ogen atom or an alkyl or aralkyl radical and R 6 represents a hydrogen atom or an aralkyl, aryl, heteroaryl, alkyl, alkenyl, alkinyl, alkoxy, in which alkenoxy, alkihoxy, alkylene, dioxyalkylene, halogen, monofluoroalkyl, polyfluoroalkyl, mono- fluoroalkoxy, polyfluoroalkoxy, hydroxyl,, amino, ~alkylamino, r,tro, cyano, azido, carboxyl, carbalk- in an inex oxy, carboxamido, sulphonamido or 0- -alkyl (in bindiing aE which m is 0, 1 or 2) radical, in which the aryl, water beir alkyl and heteroaryl radical can in turn be b) a1,4 substituted by one to three identical or different formula radicals selected from aryl, alkyl, alkoxy, aralkyl, dioxyalkylene, halogen, monofluoroalkyl, polyfluoro- alkyl, monof-luoroalkoxy, polyfluoroalkoxy, hydroxyl, amino, alkylamino, nitro, cyano azido, carboxyl, carbalkoxy, carboxamido, sulphonamido and SOMalkyl in which (in which m is 0, 1 or 2). I According to the pF esent invention we further me ar provide a process for the production of a compound of the is reacted invention," in which formula a) a hydroxy-1,)4-dihydropyridine derivative of the general formula inwhich

Rio )OC X-OH X.ha (II) Z an and A3 wherein RhC in a molara Le A 20 638

-17

medical administration and may be, for example, any in the metf of the following: tablets (including lozenges and Darenteral organic in whict, a water-t and 180 0 C n ,R1, R 2 ,Rig' F4 j Y,7and X nave the above- mentioned meanings, which Y a is reacted with an equivalent amount of dihydropyridine- 5 obtained 3-caroxylc d derivative of tht generail formu'a C) an YJ

(Ii

2 R3 in which 4 in whichi R R3 R, 10 islreacte, RI,R R. R3 .;IFI'R and Y' have the above- mentioned meanings, but Y' does not represent general f IC a carbonyl. group, in an inert organic solvent in the presence of ;a-water- Linding agent At a temperature between 0 0 C and 1800C, water being split off, or L) a l4-dihydropyridirecarboxyl-ic acid uf the general irn which f orm.ula

R 0'oc C0OH in a mola2 (IV) 2I organic sc R~ PrE in which compounds 41I -R HR,3 R R and Rhave the abovementioned 20 R 4 and FR meaning, variant c) Sis reacted with a bifunctional compound of the general in whi f ormula prepared b z-x-z' The (V) 25 according in which X has the abovementioned meaning and properties Z and V are in each case identical or different inf luencin and repre<sent hydroxyl, mercapto or a NH-R5 radical agents, as wherein as coronar 5 has the R. abovementioned meaning, 30 exhibit pa in a molar ratio of about 2-1l in the presence of an inerzt Le A 20 63

Le A 20 638

18 in the method of the invention is preferably oral or I nri z nn Cl- be regarde organic solvent and, if ppropriate, in the presence of Com a water-binding agent, a I a temperature between 00C the invent and 1800C, only compoundsl of te general formula in in which which Y and Y' do not repliesent a carbonyl group being R a obtained by this variant,',or ah c) an ylidene-0-keto ester of the general formula pyr R 2R (VI) thi R CH C C OR pyre 00OR 1 imic in which aryj R, R1 and R 2 have the abovementioned meanings, is,reacted with an enarinocarboxylic acid ester of the or f-on general formula cyc2 I 4 alki R -C=CHI-Y-X-Y-y' C=C-R4I (VI) >a lko R 1H HNR 3 carb ir which halo R31 'R4, R4', Y and Y' have the abovementioned me th meanings, hydr in a molar ratio of about 2:1 in the presence of an inert case organic solvent at a temperature between 000 and 18000. carb Preferably symmetric compounds, that is to say sulp- compounds in which in each case Y and R 3 and R31 and with R and R are identidal, are prepared by this process radic variant Symmetric compounds of the general formula H1 ar in which Y denotes a carbonyl group can also be repre prepared by this process variant c). satur The dihydropridines of the general formula (I) has u according to Ihe invertion have valuable pharmacological inter properties. By virtue of their circulation- and i influencing action, they can be used as antihypertensive hydro agents, as vasodilators, as cerebral therapeutic agents and sulph as coronary therapeutic agents. Surprisingly, they being exhibit particularly long-lasting actions and are thus to

Le A 20 638 Le A 20 638

-19 50 mmole be regarded as an enrichment of pharmacy. Compounds of the general formula according to the invention which are of particular interest are those in which R and R'.crepresent a phenyl or naphthyl radical or a heterocyclic radical selected from thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benz- 10 imidazolyl, quinazolyl or quindxalyl radical, the aryl or heterocyclic radical optionally carrying 1 or 2 identical or different substituents selected from phenyl, alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, alkenyl or 1 alkinyl with in each case 2 to 6 carbon atoms, ,alkoxy, alkenoxy or alkinoxy with in each case up 'to 4 carbon atoms, an alkylene chain with 3 to 6 carbon atoms, dioxyalkylene with 1 or 2 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, difluoro- methoxy, tetrafluoroethoxy, nitro, cyano, azido, hydroxyl, amino, mono- or di-alkylamino with in each case 1 to 4 carbon atoms per alkyl group, carboxyl, carbalkoxy with 2 to 4 carbon atoms, carboxamido, sulphonamido and sulphonylalkyl or alkylmercapto with in each case 1 to 4 carbon atoms per alkyl radical; 1 1' R and R are identical or different and each represent a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbun radical which 3L has up to 8 carbon atoms and is optionally interrupted in the chain by 1 or 2 oxygen atoms and is optionally substituted by fluorine, chlorine, hydroxyl, phenyl, phenoxy, phenylthio or phenyl- sulphonyl, the phenyl radicals in turn optionally being substituted by 1 or 2 identical or different

Le A 20 638 substituents selected from nitro, trifluoromethyl, cyano, fluorine, chlorine and alkyl and dialkylamino with in each case 1 to 4 carbon atoms irf the alkyl radicals; R2 R 4 and R are identical or different and each represent a hydrogen atom or a straight- chain, branched or cyclic, saturated or unsaturated hydrocarbon radical Which has up to 8 carbon atoms and is in turn optionally substituted by fluorine, chlorine, hydroxyl, phenyl, amino, alkylamino or cycloalkyl with up to 6 carbon atoms; R3 and R are identical or different and each represent a hydrogen atom or a straight-chain or branched alkyl radical which has up to 8 carbon atoms and optionally is interrupted in the chain by an oxygen atom or is substituted by hydroxyl or halogen, or represent an optionally substituted phrp yl, benzyl or phenethyl radical; Y and Y' are in each case identical or different c0 and each denote -COO-, -CONH-, -COS- or -SO 2 and X represents a bridge member which has at least one CH2 group which is not bonded to the .ings and at most 9 adjacent CH2 as chain membery, it being possible for the bridge member additionally .o contain, in any desired sequence, 1 to 4 identical or different chain members selected from 0, S, SO 2 CO, CS, NR5 C(R6)2 CR 6 CR6 CEC, CHN, phenylene, naphthylene, pyridylene and cycloalkylene or cyclo- alkenylene with>ih -ach case 3 to 7 carbon atoms, piperazinylene, piperidinylene, pyrrolidinylene and morpholinylene, wherein

R6 represents a hydrogen atom, a benzyl or phenyl Y and E radical, a fluorine or chlorine atom, an alkyl and der radical with 1 to 4 carbon atoms, a hydroxyl, X repre trifluoromethyl, cyano, carboxyl or amino radical, one CH- anralkylamino radical with 1 to .arbon atoms in thN 5 and at :Ikyl radical or a carbaltoxy radical with 1 to 4 it beir carbon atoms in the alkoxy radical. to cont Compounds of the general formula which are of ical or very particular interest are those 0, S, C in which 10 CH=N, R and R' are identical or different and cach p cycloal represent a phenyij>adAcal or a thienv,_,, furyl, azinyle naphthyl, or pyradyl radical, the phenyl radical morphol optically being substituted by one or two identical wherein or different substituents sele' cted from nitro, 15 R5 repr cyano, azido, halogen, trifluoromethyl, hydroxyl, an alky amino and alkyl, alkoxy, alkylamino and alkyl- R repr mercapto with in each case 1 or 2 carbon atoms in radical the alkyl groups, radical F 1 and R are identical or different and each represent a straight-chain or branched hydrocarbon Using t radical which has up to 6 carbon atoms and is the synthesis optionally interrupted in the chain by an oxygen according to tI and is optionally substituted by fluorine, chlorine, variants is il hydroxyl, phenyl or phenoxy, 4 41 Process variani B, Rc and F are identical or different and each represent a hydrogen atom or a straight-chain or branched alkyl radical which has up to 4 carbon atoms. and is optionally substituted by fluorine, CH3 00C chlorine_ hydrcxyl, phenyl or amino. and RW are identical or different and each CHIA represents a hydrogenatorn, an alkyl radical with 1 to L carbon atoms or a phenyl, benzyl or phenethyl radical which is optionally substituted by hydroxyl, fluorine or chlorine,

Le A 20 638 Le A 20 638

Y and Y' are in each case identical or different and denote -COO-, -CONH-, -CO- or -SO 2 and X represents a bridge member which has at least one CH, group which is not bonded to the rings0 and at most 9 adjacent CH2 groups as chain members, C it being possible for the bridge member additionally 3C to contain, in any desired sequence, 1 to 3 ident- CH 3 N

ical or different chain members selected from H 0, S, CO, CS, NR5 C(R6 CH=N, phenylene, naphthylene, pyridylene, Process variar- cycloallkylene with 5 to 7 carbon atoms, piper- azinylene, piperidinylene, pyrrolidinylene and morpholinylene, 2 x wherein H 5 C 2 0Q R" represents a hydrogen atom a benzyl radical or an alkyl radical with 1 to 4 carbon atoms, and CH R represents a hydrogen atom, a benzyl or phenyl radical, a fluorine or chlorine atom, an alkyl radical with 1 to 4 carbon atoms or a hydroxyl, trifluoromethyl, cyano, carboxyl or amino radical. Using the particular starting substances shown, HC 3 00C the synthesis of the compounds of the general formula (I) acccrding to the invention by the individual procese CH3 Svariants is illustrated by the following equations: Process variant roce variani

CHROOC COO-(CH 2 -CH 2 -H OOC O OOC 3 2 3 HOC" C00C 2H HIi 00C 1 I j O+C2H5 5 2 CH N CH3 H H2 0 CH 3 H CH 3 3

Le A 20 638 SLe Le A A 0 6')33 O 68

CF 3 K CH 3 00C (CHE2-CH -)3E c Co

H3 33H

Prbcess variart (b)

N0.l 2x

H 5 c 2( COQE HO-

CH 3 220

NO 2 NO

COOC2 H IHL 5 '0coo- a-oOC-

CEH CEH CH 3 N CHi.3 3 3 H

rocooo N variant (c)

NO 2 "I 0 0

2 occ H2 N 3Ethanol A IHC):iNH

D 1A.0 ,658 g~~Ii' I

N>.

'K II

2H

CH3

N The hydroxy-lW-dihydropyridine derivatives of the, formu&la (II) used as starting substances and the ihjrprdi ?3croy;,Lacid, derivatives of the ~rmu J(rE) are known"' or tht~y can be prepared by known methods (see DT-O S rman Published Specification) 2,111 5 71) (N The ',-l,-dihydropyridinecarboxylic acids of the general formUla (IV) are kilown, or they can be pr,'pared C 10by knq meth'ods (compare European Published Speci- 7 f~icatiQfl) 1-1, 706). Th e bifidhC±ional compounds of the general formula MV are likewise known, or they can be prepared y nw methods (s'ee Eeilstein, Volume I, )464 to 502). The- ylidene-g-keto esters of the general formula (VI) are kn-,own, or they can be-,prep-a d by pro'cesses which are known from the li~~aue(,-eG. Jones, The "Knoevenagel-Condensation"c in Organic, Reactions, Volume XV, 2014 et seq. (1967)).* The enajinocarboxylic acid esterA of the general -formula ,(VII) used: as stari;gP sUs~ r nwo ey can likewise be r'ed by method8 which are known from the itatr e A-C.Cope, J. Am. Chem. Soc. 67, l017 (94)> Possib~l.' dilue'rits for use in process 'variants (a) and' are anZP of the aprotic organic sc& Lts. These iholude, preferably, ethers (such as dloxane, diethyl ether,

.'Le A 20 638

I'

N~I

Ti

1 3.2 greatly redu tetrahydrofuran and glycol dimethyl ether), hydrocarbons vascular-spai ksuch as benzene, toluenle or xylene) and dimethylformami,.e, vascular sys dimethylsulphox'de, acetonitriie, pyridine or hexamethyl isolatted in phosphoric acid triamide. 5 example, the In the case of process.- iant alcohols (fo 4. example methanol, ethanol or isopropanol) can also normotonic a advantageously be employed as diluents. antihyperteni Water-binding agents (for process variants a d The 4b6",hvich can be used are any of the reagents customary for actions whic this, and the use of dicyclohexylcarbodiimid6 and the the stomach, addit, -6n of a catalyst, such as 14-di:.ethylaminopyridine, (,the respirat( are particularly advantageous. As si The reaction temperature can be varied within the to the use i subs'8tantial range of between,,0 and 18000, preferably between 15 pounds of th( 20aiid 1200 C. The The r(a<'Ctions canbe carried out Under noinaei comhposition pressure or under increased pressure. In general, they of the inveni are carried out under normal pressure. gaseous diluE The compounds of the present invention exhibit 20 20ther Afan interesting biological actions. They have a broad and 200 (preferat diverse pharmacologia. action spectrum and are of a surface distinguished in particular, by their long-lasting action. The.3 The fllowirg ma-aptions may be mentioned specifically: composition c 1. On parentera oral and perlingual administration, 25 of the invent the compounds produce av,distinct and long-lasting dilation logically is( of the coronary vessels This action-on the, coronary The j vessels is intensified by a simultaneous intrie-like dosage unit f effect of reducing the load on the heart. The j They influence or modify.th& heart metabolism in 30 the form of t the sense of anenergy saving. dragees, capE 2. The excitability of the stimulus formation(,nd comprising a excation conduction system within the heart is lowered, eda' so that an antifibrillation action demonstrable at physically di therapeutic doses results, 35 administratic The tone of ,12he smooth ri",le of the vessels is Le A,20 638 Le A 20 638

PI 1

26 Exnple Hpxanediy l,6 -(bis-2,6-dimethyl-5-ethoxyrbonyl-4-(3- nitrophlceiyl)l,L-dlhydropyridine -3-carboxylatej including the h

ASC-49

13 greatly reduced under the action of the compounds. This used in this vascular-spasmolytic action..can take place in the entire coherent unit vascular system or can manifest itself as more or less containing a isola'tled in circumscribed -va4cular regions (such as, for or sut>multipl example, the central nervous system). 5 of the compou 4. .he conrrrounds lower the blood pressure of a,carrier and norinotonic and-hypertonic animals and can thusbe used as the medicamen antihytpertensive agents. a half, a thi The compounds have strongly muscular-spasmolytic on whether th actions which manifest themselves on the smooth muscle of lQ or, for examp the stomach, the intpstinal tract, the uroge ital tract and day respectiv (the respiratory system. The p As stated above, the invention also relates the invention to the use in human ard veterinary medicine of te corn- (including ae pounds of the invention. 15 of the active The present invention tiovides a pharmaceutical syrups, granu comiposition containing as active ingredient a.compound The d of the invention in admixture with a solid or liquefied oo~a o positions (e. gaseous diluent, or in admixture with a liquid diluent tablets, drag other- Aan a solvent of a molecular weight less than 20 filler, a 200 (preferab-ly less than 350) except in the presence and silicic a of a surface active agent. \cellulose and The invention further ,provides a pharmaceutical gelatinee an, composition containing as active ingredient a compound aEents, e.g. of the invention in the form.,of a sterile and/or physio- 25 agi;-agar, ca logically isotonic aqueous solution. (eX agents fo The invention also provides a medicament in resorptio dosage unit form comprising a compound of the invention.-, compounds; (g The invention also provides a medicament in glycerol mono the form of tablets (including lozenges and granules),.. 30 kaolin and be dragees, capsules, pills, qipCales or suppositories and magnesium comprising a compound of the invention. The t #"Medicament" as used in this Specification means from the phar physically discrete coherent portions suitable for medical< can have the administration. "Medicament in dosage unit form" as 35 matrices, whi

Le A,20 638 Le A 20 638

27

NO,

*IW~iIY Yidzemen :Lsj a ull description of this invention, including the best met-hod 5f performing it known to me:- -*cr

1- ASC-49 I'

4 it used in tthis Specification 1 means phy ically discrete so constitute coherent units suitable foin medical administration each containing a daily dose orfi multiple (up to four times) only or prefe or submultiple (down to a f'ortieth)/of a daily dose tract, possib envelopes and of the compound of the invdntion in associatiin with a carrier and/or enclosed w 1 ithin an envelppe. Whether 5 of polymeric The i the medicament contains a d~ily dose or, for example, a half, a third"or a quart of a daily dose will d~pend encrpsulated on whether the medicament to be administered once above-me~'5 ton or, for example, twice, three times or four times a L.2e d positions ada day respectively. The pharmaceutical composition according to for example, the invention may, for exam le, take the form of sprays as polyethyle high esters (including aerosols), susp sions, solutions and emulsions or mixtures ao. of the active ingredient i aqueous or non-aqueous diluents, The p] syrups, granulates or powdgsrs. The-diluents to beiiused in pharmaceutical com- and sprays cai positions t granulates; adapt~d to be formed into e.g. lactose, calcium silic, tablets, dragees, capsules and pills include the following: filler, and extenders e.g. starch, sugars, mannitol, these substan the usual prol and silicic acid; binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, The p1 and emulsions gelatine an) polyvinyl pyrrolidone; moisturizing agents, e.g. glycerol; disintegrating agents, e.g. diluents (witl of solvents hz aezr-agar, calcium carbonate and sodium bicarbonate; in the presenc agents for retarding dissolution e.g. paraffin; resorption accelerators, e.g. quaternary ammonium solvents, disE compounds; 'surface active agents, e.g. cetyl alcohol, examples of si glycerol mnostearate; adsorptive carriers, e.g. isopropyl alcc kaolin and bentonite; lub- icants, e.g. talc, calcium alcohol, benzN and magnesium stearate and solid polyethyl glycols. The tablets, dragees, capsules and pills formed from the pharmaceutical cb'mpositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be

Le A 20 638 Le A 20 638

28

r so constituted that they release, the active ingredient glycol, direth only or preferably in a particular part of the intestinal nut oil), glyc tract, possibly over a period of time. The coatipgs, ethylene glyco envelopes and protective6'matrices may be made, for example, mixtures there of polymeric substances or waxes. For pa 5 Theingredient can also be made up in micro- emulsions shou encrpsulated form together with one or several of the isotonic. above-meKioned diluents. The ph 2 diluents to be used in pharmaceutical com- pensions can c positions adapted -o be formed into suppositories can, 10 diluents, e.g. for example, be th-6 usual water-soluble diluents, such surface-active as polyethylene glycols and fats cocoa oil and alcohols, poly I'l high esters C 1 -alcohol with C 1 6 -fatty acid)) microcrysGalli or mixtures iyf these diluents. bentonite, aga The pharmaceutical compositions which are powders 15 All the p and sprays can, for example, contain the usual diluents, the invention e.g. lactose, talc, silicic acid, aluminium hydroxide, preservatives calcium silicate, and plyamide powder or mixtures of peppermi these substances. Aeroso l sprays can, for example, contain agents s the usual propellants, e.g. chlorofluorohydrocarbons. 20 The ph The pharmaceutical compositions which are solutions the invention and emulsions can, for example, contain the customary active ingredi diluents (with, of course, the above-mentioned exclusion In add of solvents having a molecular weight below 200 except the pharmaceifi in the presence of a surface-active agent), such as 25 to the inventi solvents, dissolving agents and emulsifiers; specific active compour examples of such diluents are water, ethyl alcohol, of compounds c isopropyl alcohol, ethyl carbonate,,ethyl acetate,benzyl Any di alcohol, benzyl benzoate, propylene glycol, 1,3-butylene invention may to the pharmac Such medicamer less than 200 The di the medicament be adapted by

Le A 20 638 Le A 20 638

iii

29

e NO,

Le" A 20 63E

16 medical admini glycol, dimethylformamide, oils (for example ground of the followi nut oil), glycerol, tetrahydrofurfuryl alcohol, poly- granulates), p ethylene glycols and fatty acid esters of sorbitol or and ampoules. mixtures thereof. delayed releas For parenteral admiistration, solutions aid as capsules, i emulsions should be sterile, and, if appropriate, blood- the portions o isotonic.. and coherent. The pharmaceutical compositions which Pre sus- '".The pr pensions can contain the usual diluents, such as liquid administration diluents, e.g. water, ethyl alcohol, propylene glycol, 2.5 mg to 250 surface-active agents ethoxylated isostearyl administration alcohols, polyoxyethylene sorbite and sorbitang esters), 250 mg of actii microcrystalline cellulose, aluminium metahydr xide, The pr( bentonite, agar-agar and tragacanth or mixtures thereof. 15 ceutical compoE All the pharmaceutical compositions according to by any method the invention can also contain colouring agents and the active ing: preservatives as well as perfumes and flavouring additions a pharmaceutice peppermint oil and eucalyptus oil) and sweetening then forming ti agents saccharin). tablets). The pharmaceutical compositions according to This ir the invention generally contain from 0.5 to 90% of the combating, (inc. active ingredient by weight of the total composition. the above-menti In addition to a compound of the invention, animals, which the pharmaceUJ\ical compositions and medicaments according 25 a compound of t to the invention car, also a'ntain other pharmaceutically a diluent or ir active compounds. They may also contain a plurality the invention. of compounds of the invention. It is e Any diluent in the medica n of the present will be adminiE invention may be any of those ment-';oned abcve in relation 30 intramuscularly to the pharmaceutical compositions of the present invention. intravenously), Such medicaments may include solvents of molecular weight parenterally, i less than 200 as sole diluent. Preferred pharn The discrete coherent portions constituting are therefore t the medicament according to the invention will generally as oral or pare be adapted by virtue of their shape or packaging for

Le A 20 658 Le A 2o 638

-i y)

Le A 20 638 Le A 20 638

17 medical administration and may be, for example, any in the met of the following: tablets (including lozenges and parenteral granulates), pills, dragees, capsules, suppositories In and ampoules. Some of these forms may be made up for L.ntravenous delayed release of the active ingredient. Some, such 5 ably 0.05 IT as capsules, include a protective envelope which renders administer the portions of the medicament physically discrete 0.5 mg to and coherent. effective r 'The preferred daily dose for intravenous be necessar administration of the medicaments of the invention is 10 in particul mg to 250 mg of active ingredient, and for oral body weight administration of medicaments of the invention is 25 to the individ 250 mg of active ingedient. the type of The production of the above-mentioned pharma- is administ 15 is carried ceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing disease or the active ingredient(s) with the diluent(s) to form Thus it may a pharmaceutical composition a granulate) and above-menti then forming the composit'lon into the medicament (e.g. the upper 1 tablets). 20 the desired This invention further provides a method of it can be a: combating, (including prevention, relief and cure of) administrat: the above-mentioned diseases in human and non-human Prol animals, which comprises administering to the animals to the presi a compound of the invention alone or in admixfure with 25 Examples. a diluent or in the form of a medicament according to Example 1 the invention. Butanediy1 It is envisaged that these active compounds phenyl)-l,4 will be administered perorally, parenterally (for example 30 3-carboxyla intramuscularly, intraperitoneally, subcutaneously and intravenously), or rectally, preferably orall or parenterally, in particular perlingually or intravenously. Preferred pharmaceutical compositions and medicaments are therefore those adapted for administration such as oral or parenteral administration. Administratior

Le A 20 638 Le A 20 638

i: .i o a 1uu n the presence of an inert

'Le A 20 638

18

in the method of the invention is preferably oral or parenteral administration. In general it has proved advantageous to administer intravenously amounts of from 0.01 mg to 10 mg/kg, prefer- ably 0.05 mg to 5.mg/kg, of body weight per day or to administer orally from 0.05 mg to 20 mg/kg, preferably mg to 5 mg/kg, of body weight per day, to achieve effective results. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature ad body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered-and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered

it can be advisable to divide these into several individual administrations over the course of the day. Processes for the production of compounds according to the present invention are illustrated by the following Examples. Example 1 Butanediyl l-[2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitro- phenyl)-1, 4-dihydropyridine-3-carboxylate 4- [2,6-dimethyl- 5-methoxycarbonyl-4-(2-chlorophenyl)-l,4-dihydropyridine- 3-carboxylate] t;Aiuub par~icuiariy long-lasting actions and are thus to

Le A 20 638,

C,

H5C2 00C Coo0-(C )oo0c COOCH 3

CH C N CH3 CH 3 H 3CH 3 H

(Process variant mrnoles of 2,6-diinethyl-5-(4-hydroxybutoxy)- carbonyl-4- (3-nitrophenyl)-1, 4-dihydropyridine-3-carboxylic acid ethyl ester wer'e dissolved in 50 ml of anhydrous diinethylformamide together with 25 inmoles ol dicyclohexyl- carbodiimide and 25 inmoles of 2,6-dimethyl-5-methoxy- carbonyl-14-(2-chlorophenyl)-1,14-dihydropyridine-3-carboxylic acid -and the solution was heated to 100 0 Cfr1 orwt the addition of 0.2 g of 4-dimethylaminopyridine. The mixture was then filtered and the filtrate was diluted with mnethylene chloride, extracted by shaking with aqueous NaOH and with HC1, dried, and concentrated in a rotary evaporator. The residue was then chromatographed on silica gel using ether. Yield: 25%, amorphous foam. 1H-NvRn: 6 1.2 1.14-1.8 (mn, 4H), 2.4 (s,12H-), 3.6 3.9-14.4 5.2 5.14 (s,lH), 5.8 6.3 (s,NH) and 6.9-8.3 (m,8H). Example 2 1exanediyl 1,6-bis- 26dmtyl'--ehxyabnl4 (3-nitrophenyl 4-dihydropyridine-3-caxboxylate.I NO2 No

H 5 C2 00C COO-(CH 2 6 -00C 1 COOC 2 H CECEN CH3 3 H 33H (Process variant

Le A 20 638 an alkN beig Shsttutd Y 1 or 2 identical or different

Le A 20 638 Le A 20 63'8

20 mmoles of 2,6-dimethyl-5-met.hcxycarbonyl-4- (3-nitrophenyl)-l,'4-) -'hydropyridife--Carboxylic acid were dissolved in 50 ml of anhydrous dimethylformamide together with 50 mmoles of dicyclohexyJlcarbodiimide and H;sc 2 00C 25,rnoles of hexane-l,6-diol and the solution was stirred at 100 for 4 hours, with the addition of 0.2 g of N CH 3 H 4-dime thy laminopyridine. The mixture was then filtered, the filtrate was diluted with methylene chloride, Analogous: extracted by shaking with aqueous NaOH and with HCi, dried, and concentrated in a rotary evaporator, and the residue pyridilie-3-carbox was recrystallised from methanol. 5 'triethylene glyco' Melting point: 177-179%, yield: 37%. Melting, point: 1 Example 3 Example Prop anediy 7b-is -[2,6-dimethyl-5-methoxycarbonyl- 1 4- Decanediyl 1,10-b: (2-chloropheniyl)-1,14-dihydropyridine-3-carboxylate] (3-nitrbcphenyl) -1

COO- (CH 2

CH C H CH "-N-CH 3 .110 H5 c2 0c, 3 H 3 H (Process variant CH 3 mmoles of propanediyl l,3-bis-(3-aminocrotonate.,) and 50 mmoles of 2-chlorobenzylideneacetoacetic acid 100 mmole methyl ester in 100 ml of absolute ethanol were boiled (3-nitrophenyl )-l under reflux and under N2 for 14 hours. reacted with 50 N After the mixture had cooled, the solvent was to Example 2. distilled off in vacuo and the residue was taken up in 15 Melting point: a strength aqueous ethanol,, The semi-solid residue Example 6_ was recrystallised from methanol. Octanediyl l,8-bi Melting point: 200 to 20300; yield: 50%. nitropheny1-1, 4-t Example 4 Triethylene glycol bis-[2,6-dimethyl-5-methoxycarbonyl- (3-ni tropheny)-l1, 4 -dihydr opyrid ine 3-carb oxy lat e]

Le A 20 638 Le A 20 638

,an alkyl radical with I. to 4 carbon atoms and by hy Le A 20 658 Le A 20 638

21

NO2 NO2

c 200C COO- (CH2 -CH 2 3-0c. C000 2 IL

H3 H c 000 CH3 CH3 CH 3 CET, Analogousliy to Examp*Le 2, 100 mmoles of 2,6- dimethyl5ethoxycarbonyl-4(3itrophenyl)l4dihydro- Analogo, pyridii'e-3-carboxylic acid were reacted with 50 mmoles of 'triethylene glycol and the mixture was worked up. pyridine-3-carb( Melting point:.. '13 to 120 00;, yield. 52%. 5 J.,8 -octanediol. Example 5 Melting point: Decaned: ,yl 11-i 26-iehl5ehoyabnl4 Example 7 (3-nitrophenyl)-l,t4-dihydr0pyridine-3-Carboxylatel Pentanediyj. NO (5-ni tropheny 1-:

COO- (OH 2 1 o OOC 0000 H5c2 OH3 'CH3 Hsc 2 0c" 1 C3 H CH 3 100 mmoles of 2,6-dimethyl-5-ethoxycarbonyl-4- (3-nitrophenyl)-,-dihydropyridine3-carboxylic acid were Analog ou reacted with 50 mmoles of l,10-decanedio'l analogously to Example 2. pyridine-3-carbo Melting point: 121 to 12500C; yield: 35%. 1, Example 6 15 Melting point: 1 Octanediyl 1,8-bis- [2,6-dimethyl-5-ethoxycarbonyl4(3- Example 8 nitrophenyl-l,4-~dihydropyridine-3-carboxylate] 1, 4-bis- (2-hydro: ethoxycarbonyl-. carboxylate]

Le A 20 638 Le A 20 638 by hydroxyl, fluorine or chlorine,

Le A 206368 Le A 20 638

22

H5C2 0 0 0 N

H5 C2 00C (CH2 8 -02 C COOC 2 H5 CH H C3 HCH3 Analogouw

Analogously to Example 2, 100 mmoles of 2.,6- pyridine- dimethyl-5-ethoxycarbonyl-LI-(3-nitrophenyl)-1,i4-dihydro- 5 l,4-bis-(2-hydro: pyridine-3-carboxylic acid were reacted with 50 mmoles of Melting point:., 1,8-octanediol. Example 9 Melting point: 170 to 18400; yield: 47%. Tetraethylene gl3 Example 7 4 3-nitr op heny 1, Pentanediyl 1,5-bis- 26dmtyl5ehxcabnl4 (3-nitrophenyl-1,4-dihydropyridine-3-carboxylate]

NO2 H5 c 2 0 0

H5 c 2 COO- (CH 2 )1 COOC 2 H

CH3 CEH- -CEH CH I 3 H Analogous 3 H dimethy Analogously to Example 2, 100 rmoles of 2,6- pyridine-3-carbox dimethyl-5-ethoxycarbonyl-4W",,(3-nitrophenyl)-1,4-dihydro- tetraethylene gly pyridine-3-carboxylic acid were reacted with 50 mmoles of 15 1,5-pentanediol. Melting point: Melting point: 14500C; yield: 11/0. exanediyl 93 Example 8 1,6-bi (3-nitrophenyl)-l l1 4-bis-(2-hydroxyethoxy)-benzene bis-[21,6-dimethyl-5- ethoxycarbonyl-14-(3-nitrophenyl)-1,14-dihydropyridine- carboxylatej

Le A 20 638

Le A 20 638

Le A 20 638 Le 2658Le A2o0638

23

H5 C2 (CH 0- -00c, C00C2 H5 CHCC

CH 3 CH-.Nj., CH3 3H 3 CH3 Analogously to Example 2, 100 mmoles of' 2,6- diehl5ehxcroy--3-irpiiy)14dhdo Ag,,logouw pyridine-3-cax~boxylic acid. were reacted with 50 rmoles of' 1,6-bis- (3-aminoi 1,4-bis-(2-hydroxyethoxy)-benzene. 3-ni trobenzy lidei Melting point: 160 to 19000C (decomposition); yield: 49%. 5 Melting point: Example 9 Example 11 Tetraethylene glycol bis- LF2,6-dimethyl-5-ethioxycarbonyl- Hexanediyl 1,6-bi 5-nitropheniy1) -1,4 -dihydropyridine-5 -carb oxylatel (2-nitropheriyl

Hu OOC H5 c 2 c (CH 2 -CH 2 10OC 2 H 4- CH 3 CH3 Analogous Analogously to Example 2, 100 mmoles Of' 2,6- 1, 6-bis- (3-aminoc dimethyl-5-ethoxYcarbonyl-J4-(3-nitroplienyl)-l,4-dihydro- -ni trobenoy liden pyridine-3-carboxylic acid were reacted with 50 mmoles of' DieltinG point: 8 Example 12 c> up. tetraethylene glycol and the mixture was worke 15 Hexanediyl bis [2 point: 93 to 9800 yield: 165. Example 10 obloruphenyl 4 Hexanediyl 1,6-bis- [2,6-dimethyl-5-isopropoxycarbonyl-4- (3ntohnl-,-iyroyiie3croyae

CH 3

Le A 20 638 Le A 20Q 638

NO2 'NO 2

COCCOO- 0H (CH -OOC/ o CH 3 I HCC2'6- COO-CE CHE3 IIH C3 N CEHC E

A~blogously to Example 3, 25 irmoles of hexariediyl l,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of 3-nitrobenzylideneacetoacetic acid diisopropyl ester. Mvelting point: 120 to 13600 yield: 83%. Example 11 Hexanediy. 1,6-bis-[L-,6-di.methyl-5-methoxycarbonyl-4- (2-nitropherlyl)-l,4-dihydropyridirie-3.-carboxylateI

(002 0NO 2

CH 3 'OC (COO-(CE2 )6_0 COOOO

CH NE CE N 3 An~alogousl~y to Example 3, a5 mmoles of hexanediyl 1,L-bis-(3-aminoczrotonate) were reacted with 50 mmoles of >nitroberizylideneacetoacetic acid methyl ester. N~ultir.Z point: 88 to 950 C yield: 82%. Example 12 Hexarnediyl bis- [2,6-dimethyl-5-methoxycarbonyl-4-(2- clhlorophieny 1)-1 4-dihydropyridine- 3-carboxy late'

O C1 0 C CH 3OOC. 00- (CH2 6 _ooC 'OOCH

CE N 3 C N H 3 H3

Le A 20 638

Analogously to Example 3,25 mmoles of hexanediyl l,6'-bis-,(3-aminocrotonatb)'were reacted wit 50 mmroles of 2-chlorobenz pli25! neacetoacetic acid methyl ester. Melting point: 152 to 15800; yield: 27%. am'le 13 y 2-yrobxyetyl)-piperaxine bis-f2,6-dimethyl-

c axb ox y 1la 1-el *NO 2 O

2 oor Hc COO-CE 2 -C CH -CH -00 COOC H

:bCH 2 CEH N 3 C3 N CE 3 H H

Analogously to Example 2, 100 mmoles of 2,6- "hoxycarbcnyl- 1 l-(3-nitrophenyl)-1,4-dihydro- acid were reacted with 50 mmoles of N,,N'b is 7(2-hydr oxy ethy1)-p iperaz inte. Melting point: to 20800 yield: 181o. ample VJj is-hydrqxyethyl sulpbide bis-[2,6-dimethyl- ",-ethoxycar- bon'l-4-(-,Y irdpenyL Ll,4dihydropyridine-3-carboxylateJ NOO

H5 C2 OOCCOO-CH 2 -CH 2 S-CE 2 CH-C 0

CEH N CH, C 3 N H3

Analogously AGb Example 2, 100 mmolies of'-2,6

irridihne-3-carboxylic acid were reacted with 50 mmoles of 'is-hyaxr'oxyethyl, sulphide. ~ield: 707,"

Le A 20 63Q3

Le A 20 638

-26

Exjaple Hfxanediyli. l,6- bis- [2,6-dimethyl-5-ethoxyc'arbony>lvC4-3- nitrophaiyl)l,L-dihydropyridine-3-carboxylate.j

3 0CFC2 F3 H C,0COU-(CH2 )6_00C COOC I Ile C Nj H3 3 Anal Analogously to Example 3, 25 r nole6 of hexanediyl 1,6 -bi,,--(37-aminocrotonate) were reacted with 50 mmoles of 2-trifluoromiethylbenzylideneacetoacet ic acid ethyl ester. Melting poair Melting point: 129 to 139 OC yield 49%. Example 18 Example 16 1C Hexanediyl 1,6-bis- [2,6-dimethyl-5-(2-methoxy)-ethioxy- ethoxycarb'on carbonyl- 1 -(3-nitrophenyl)-l,4-dihydropyridine-3-carboxy- carboxylate lat] O NNO 2

H5 C2 00C CU3 0-CH 2 -'cH 2 000 00-(CH 2)E HUN ICu3 3 N 3 Cf3 T4T Anal Analo )ously to Example 3, 25 mmiles of hex anediyl l;6U"-bis-(3-ap~nocrotbonate) were reacted with 50 M ,6,'sof carboxylic a 3-niitroben,-,ylideneacet'oacetic acid 2-methoxy ethyl ester. Qaydroxymethy: Melting,'I oint: 144 to 156 0 C yield.: 50%. 15 Melting poini Example 17 Example 19 Hexanedi,'tI 1. 6-bis-[C.6-dimethyl-5-methylcarbonyl-4- 1,4-iis-(hydi 210 (L,--cloro -ntrophenyl)-l,4-dihydropyridine-3croy I ethoxycarbon3 1la tej 3-carboxylatE

Le A 20 638 ,Le A 20 638

1~

38 alky2mercapto with in-each case 1 to 4 carbon atoms per bel alkyl radical; -1 11

.Jc; m£aJ v Ql,

27

H 5 c 2 00CI CH 3 (CH 2 6 CH 3

Anal( Analo~ously to Example 3 25 mmoles// exanediyl l,6-bis'-(3-am-inocrotonate)('were reacted with~ 50 mrnoles of pyridine-3-cE 2-chloro-5-nitro-benzylidene-2<, 4-butanedione. 5 1, 4-bi s -(hydi "~Melting point:-147 to 153 0 C yiei'd: 46%. Melting point Example 18 r Example E-1,4-Bis(hydroxyrethyl)cyclohexane bis-_j2,6-dimethyl-5- Hexanediyl 1, ethoxycarb'onyl-LI-(3-nitrophenyl)-l, 4-dihydropyridine-3- (2-cyariopheny carboxylatej N0

H5 C2 00C COO-CH 2 1111iHi20 H5 c 2 c CJC H

FH N trans C 3 NH 3

Analogously to Example 2, 50 mmoles of 2,6-dimethyl- Analo 5'<-thoxyarbonyl-L-(3-nitrophenyl)-1,4dihydropyridine-3- l,6-bis- [3-am. carboxylic acid were reacted with 25 mmoles of E-1,14-bis- 2-cyanobenzyl: (bydroxymethyl)-cyclohexane. Yield: Melting point: 172 to 18800 yield: 15%. 15 Example 21 Example 19 1,4-BTis(hydroxymethyl)-benzene bis- [2,6-dimethyl-5- dihydropyrid ii ethoxycarbony-14- (3-hitrophenyl)-l, 4-dihydropyridine- 3-carboxy,,ate]

Le A 20 638 .Le A 20 638

i 9 being possible for~dthe bridge member additionally L% contain, in any desired sequence, 1 to 4

Le A 20 638

28

H5 C2 OOC.

CU ~N HU

Analogously to Example 2, 50 mmoles of 2,6- dimethyl-5-ethoxycarbony--4- (3-nitrophenyl 4-dihydro- pyridine-3-carboxylic acid were reacted with 25 mmoles of 1,4-bis-(hydroxymethyl)-benzene. Melting point: 2144 to 5900C yield: 350%. Example 0 Hexanediyl l,6-bis-j.2,6--dimethyl-5-ethoxycarbonyl-4- (2-cyanophenyl 4-dihydropyridine-3-carboxylateI

0N H5 C2 000 00- (C 2 6 -00C. U -2

CH 3 N U3

Analogously to Example 3, 25 mmoles of hexanediyl l,6-bis-[3-aminocrotonate) weive reacted with 50 mmroles of 2-cyanobenzylideneacetoacetic acid ethyl ester. Yield: Example 21 Bis-[2,6-dimethyl-5-ethoxycarbonyl-I-(3-nitroph Inyl)-1,4- dihydropyridine-3-carboxylic acid] l,6-hexanedix \..amide

Le A 20 638

Le A 20 638 Le A 20 638

29

INO2 NO 2

02 000 I115 CO-NH-(0H 2 6-NH--OC c0002 H5 H 5 C2 00C

CH 3 CH3 CH3 N OH3 CH3 H Analogously to Example 2, 25 mmoles of 2,6-dimethyl- This 1 4- (3-nitrophenyl 4-dihydropyridine- 2 from N,N'-h 3-carboxylic acid were reacted with 12.5 mmoles of 1,6- eth oxy carb ony diarinohexane. 5 carboxylic ac Yield: 27% (melting point: 1)47 to 1520C). Yield: 32%', Example 22 Example 214 Octanediyl l,8-bis-[2,6-dimethyl-5-methoxycarbonyl-1- Bis- (2-hydrox (2-chlorophenyl)-l,14-dihydropyridine-3-carboxylate] methoxycarb cn 3-carboxylate

OH 000 C OOO-(0H2 8-OOc COOOH3

3 N O 3 OH3 Nl~NIsOH 3 OH 000 1 H 7 H Analogously to Example 3, 25 mmoles of hexanediyl OH 3 l,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of 2-chlorobenzylideneacetoacetic acid methyl ester. This( Yield: 80% of amorphous substance. 3 from bis-(2- 1H-NMvR (ODC1l3): 8 1.0-1.14 (in, 8H), 1.14-1.7 (in, 4H), and 2-nitrober 2.2 (2s, 12H), 3.6 6H), 4.0 L4H), 5.14 2H), 15 Yield: 80% of 5.9 NH) and 6.9-7.5 (mn, 8H). 1 H-NMR(ODC., Example 23, 6H), 3.9-i N,Nt -Bishydroxyethylurea bis- [2,6-dimethyl-5-ethoxycarbonyl- 7.1-7.8 (in, 8F~ 4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateI Example Hexanediyl 1,6 carbonyl-14- (2- carb oxy late]

Le A 20 638 Le A 20 63,8

41 is reacted with a inv, to anv of claims 1.tc )4 i hir'b) ue du: CLCP~= Uyf v ±LvU it- VA. LIICLj. Q

Le A 20 638

H5 2 00C COO-(CH 2 2 -NH- -NH-(OH 2 2 -OOO COOO2 H

CH N OHCHOCH H O 3 3 H This compound was prepared analogously to Example 2 from N,N1 -bishydroxyethylurea and 2,6-dimethyl-5-

carboxylic acid. Yield: 3216%, melting point: 178 to 18700. Example 24 Bis-(2--hydroxyethyl)-sulphide bis-[2.6--dimethyl-5- miethoxycarbcrnyl-4- (2-ritrophenyl 4-dihydropyridine- 3-carboxylate]

0110 NO2 102 OH 3000 O-(OH 2 S-(OH2 2 2 -000 OOOH3

OH 3 N OH OH 3 N OH 3

This compound was prepared analogously to Example 3 from bis-(2-hydroyyethyl) sulphide bis-(3-aminocrotonate) and 2-nitrobenzy leneacetoacetic acid methyl ester. Yield: 80% of amorphous substance 1 H-NMvR (OD~l3 8 2.3 (2s, 12H), 2.4-2.8 (in, 4H), 3.6 (SA 6H)3 3.9-4.3 (in, 4H), 5.8 (s3 2H), 6.3 NH) and 7.1-7.8 (in, 8H). Example 2 Hexanediyl 1,6-bis- [2,6-dimethyl-5-(2-methoxy)-ethoxy- carbonyl-4-(2-chlorophenyl)-1,)4-dihydropyridine-3- carb oxylate]

Le A 20 63,8 eA2068Le Le A 20 638 A 20 638

.7.9

31

0 01 CH 3 -(CH 2 2 000 COO-(CH 2 6 -OOoI

I I CH CH 3 H 5 C 2 00C Ch N CH 3 3 3H This compound was prepared analogously to Example 3 f om 25 mmoles of hexanediyl l,6-bis-(3-aminocrotonate) Ana' and 50 mrnoles of 2-chlorobenzylideneacetoacetic acid (2-hydroxyel 2-methoxyethyl ester. of 2,6-dimei Yield: 67% (melting point: 135 to 143 C). 5 dihydropyric Example 26 Yield: 77% 1 H-NMR Bis-(2-hydxroxyethyl)-sulphide bis-[2,6-dimethyl-5- (CDC: ethoxycarbonyl-1 4- (2-trif luoromethylpheniyl) -1,4l-dihydro- pyridine-3-carboxylate] 7.2-8.2 (in, Example 28

HO caCF3 Qa CF 3 Octanediyl I bonyl)-14-(3- H5 C2000 COO-(CH 2 S-(CH 2 OC COOC H5 2 2 at e]

3 H 3 H3 CCH N CH3 This compound was prepared analogously to Example CH30-(CU 2,)2,-000 3 from 25 mmoles of bis-(2-hydroxyethyl)-sulphide bis- (3-aminocrotonate) and 2-trifluoromethylbenzylidene- CH 3 acetoacetic acid ethyl ester. Yield: 79% of amorphous substance. 15 Anal, 1 H-Nr4R (C~DC 8 3 1.2 6H), 2.2 12H), 2.4-2.8 l, -bis,-(3-ai (in, 4H), 3.9-14.5 (in,8H), 5.6 2H), 6.7 NH) and 50 rnxroles of 7.1-7.7 (mn, 8H). ethyl ester. Example 27 Yield: Bis-(2-hydroxyethyl)-disulphide bis-[2,6-dimethyl-5- 20 Example 29 ethoxycarbonyl---(3-nitrophenyl)-l, 4-dihydropyridine- 3-carboxylatel (2-inethoxyetl pyridine-3-ce

Le A 20 638 Le A 20 638

Le A 20 638LeA2 Le A

32

-NO2

Ch 3 0-(CIh2 )i

c2000 COO- (CR2 2 (012)2-000 CH3

R3 'C 3 COH H3 CKN This cc 3 from 25 mmolE Analogously to Example 2, 12.5 mmoles of bis- (2-hydroxyethyl)-disulphide were reacted with 25 mmoles (3-aminocrotonz 5 acetoacetic ac: of 2.,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-,4- Yield: 67% (r, ~dihydropyridine-3-carboxylic acid. Example Yield: 77% of amrophous substance. 1 H-NMVR (CDC Bis- (2-hydroxyc 3 6H), 2.4 12H1), 2.7-3.1 methoxyethoxyc, (in,4H1), 3.9-4.5 (mn, 8H1), 5.1 211), 6.4 NH) and 10 dihydropyridinE 7.2-8.2 (in, 8H). Examiple 28 Octanediyl 1,8-bis- [2,6-dimethyl-5-(2-methoxyethoxycar- bonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxyl- CH3 -(CR 2 2 ate] NO 2 116 S y NO 2 CH -Ne 'This col 0110- (CR2 2 -1 COO- (012 )8000c (0H 2)2-00113 Yield*. 28% (me' CH3 0CH Example 31 Octanediyl 1,8-1 Analogously to Example 3, 25 mnioles of octanediyl (l-naphthyl lB-bis-(3-aininocrotonate) were reacted together with minoles of 3-nitrobenzylideneacetoacetic acid 2-iethoxy ethyl ester. CR 3000 Yield: 75% (melting point: 146 to 15000C). Example 29 N- 0CH3 l',4-Bis-(hydroxymethyl)-benzene bis-[2,6-diinethyl-5- 3 H This cc (2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydro- Yield: 76% of pyridine-3-carb oxy late]

Le A 20 638 Le A 20 638

'44 ijrocess variant

Le A 20 638

-33-

N02 NO2

Ch 3 0-(Oh2 E 00 COO-CH2 C12 -00O COO- (oH2 2-OH3

CH 3 N OH 3CH 3 C 3 This compound was prepared analogously to Example 3 from 25 mmoles of l,4-bis-(hydroxymethyl)-benzene bis- (3-amirnocrotonate) and 50 mmoles of 3-nitrobenzylidene- acetoacetic acid 2-methoxyethyl ester. Yield: 67% (melting point: 159 to 16200). Example Bis-(2-hydroxyethyl)-sulphide bis-[2,6-dimethyl-5- (2- metho)cyethoxycarbonyl)-4-(2-trifluoromethylphenyl)-l,4-. dihydropyridine-3-carboxylatej

C3 CF CH3 0-(0H 2 2 -O0O 000-(CH 2 2 -S-(0H 2 2 -000 00-(0H )-0CH 3

OH 3 N OH 3CH 3 N OH3 H H This compound was prepared analogously to Example 3. Yield: 28% (melting point: 100 to 11200). Example 31 Octanediyl 1,8-bis- 26dmty--etoyabnl4 (l-naphthyl)--1A--dihydropyridine-3-carboxylate]

CH 3 000 rO-(0H 2 8 -000-- 000H3 OH OHCH- OH3 Ct3 uN HH3 This compound was prepared analogously to Example 3. Yield: 76% of amorphous substance.

Le A 20 638 Le A 20 638 3

34 0 11-NMR_(CDCl) 0.8-1.5 (in,12H), 2.3 (2s, 12H), 6H), 3.6-4.1 4H), 5.8 2H), 6.1 NH) and 7.1-7.8 141). Among the new 1,4-dihydropyridine compound salts of the invention, those salts that are pharmaceutically acqceptable are particularly important and are preferred. The new free 1,4-dihydropyridine compounds of the i*eneral formula and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art. The present invention also comprises pharmaceutic- ally acceptable bioprecursors of the active compounds of the present invention. For the purposes of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound. New 1,4-dihydro: position, their

Le A 20 638 RTF Le A 20 638

Le A 20 638 Le A 20 638

BAYER AKTIENGES3ELLSCAF~T

New 1,1 -dihydropyridine compounds linked in the C-7) position, their production and their medicinal use.

Le A 20 638 RTF

Le A 20 638

Le A 20 638

The claims defin.- 1. CompoundE linked in the

R2-

or a salt thereof in which Rland RI rep re sen't radical s pyrazoly]. thiazolyl pyraziny2. v indolyJ.,I the aryl optionall substituer alkoxy, a: monofluorc polyfluorc.

ntrocyo carboxarnid Mn is 0$ 1

represent saturated which is 0 1 or 2 oxy

phenoxy, p in turn is dialkylai

Le A 20 638

Claims (1)

1. Le A 20 638

   35

   The claims defining the invention are as follows 1. Compounds which are 1,4-dihydropyridines which are linked in the C-3 position, of the general formula R RI R 100C Y X-Y' COOR1 (1)

   2 1 22 4 12 11 R2 R N R N R 3 R R' R R or a salt thereof, in which R and R' are identical or different and each represeni;t an aryl radical or a heterocyclic radical selccted from thienyl, furyl, pyrryl, pyrazolyl, i Ii 4.dazclyl, oxazolyl, isoxazolyl, thiazolyl, pyiidyl, pyridazinyl, pyrimidyl, pyrazinyl, quilyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl and quinoxalyl, the aryl radical or the heterocyclic radical optionally containing 1 to 3 identical or different substituents selected from phenyl, alkyl, alkenyl, alkoxy, alkenoxy, alkylene, dioxyalkylene, halogen, monofluoroalkyl, polyfluoroalkyl, monofluoroalkoxy, polyfluoroalkoxy, hydroxyl, amino, alkylamino, nitro, cyano, azido, carboxyl, carbalkoxy, carboxamido, sulphonamido and SO-alkyl (in which m is 0, 1 or 2), i 1' R and R11are identical or different and each represent a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally interrupted in the chain by 1 or 2 oxygen atoms and which is optionally sub- stituted by halogen or hydroxyl, or by a phenyl, phenoxy, phenylthio or phenylsulphonyl group, which in turn is optionally substituted by halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or

   Le A 20 638

   CH 3 C N H 3 H 3 H 3 H

   Le A 20 638

   36 S nitro, R2 R2 R and R are identical or different and each represent a hydrogen atom or a straight- chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally substituted by halogen, hydroxyl, aryl or amino, or represent an amino group, which in turn is optionally sub- stituted by a hydrocarbon radical, and this hydro- carbon radical can be straight-chain, branched or cyclic and saturated or unsaturated and is in turn optionally substituted, R 3 and R 3 are identical or different and each represent a hydrogen atom or an optionally substit- uted straight-chain or branched alkyl radical which is optionally interrupted in the alkyl chain by one or two oxygen atoms, or represent an optionally substituted aryl or aralkyl radical,, Y and Y' are in each caae identical or different and each denote 0 0 0 0 I! ti It II or -SO 2 and X represents a bridge member with at least one CH2 group and at most 9 adjacent CH groups, it being possible for this bridge member additionally to contain, in any sequence, 1 to 5 identical or 2 different chain members selected from 0, S, SO, SO, CO, CS, NR5 C(R 6 )2,CR 6 CR6 C C, CHIN, arylene, beteroarylene, cycloalkylene, cyclo- alkenylene, piperazinylene, piperidinylene, pyrrolidinylene and morpholinylene, wherein R5 represents a hydrogen atom or an alkyl or aralkyl ra ical and R represents a hydrogen atom or an aralkyl, aryl, heteroaryl, alkyl, alkenyl, alkinyl, alkoxy, alkenoxy,

   Le A 20 638 alkinoxy, a gylene, dioxyalkylene, halogen, mono- fluoroalky,$' polyfluoroalkyl, monofltuoroalkoxy, polyfluroalkoxy, hyd~ioXyl, amino, alkylamino, Pnitrr., cyano, azido, carboxyl, carbalkoxy, car- b'u' amido, suiphonamido or SO M-alkyl (in which m is 03 1 or 2) -,ad-*Lcal, in which the aryl, alkyl and heteroaryl radic-l can in turn be substituted by one to three identical or different radicals selected from aryl, alkyl,.alkoxy, aralkyl, dioxy- alkylene, 'alogen, monofluoroalkyl, polyfluoro- alkyl, monofluoroalkoxy, polyfluoroal1koxy, hydroxyl, amino, alkylamino, nitro, cyano, azido, carboxyl, carbalkoxy, carboxamido, sulphonamido and SO m alkyl (in which m is 0, 1 or 2) 2. Compounds according to claim 1, in which R and R' represent a phenyl or naphthyl radical or a heterocyclic radical selected from thienyl, furyl, pyrryl, pyrazolyl, 'imidazolyl, oxazoly'',., isoxazolyl, thiazolyl, pyridyl,- pyridazinyl, pyrimidyl, pyrazinyl, quit.ol1yl, i-soquinolyl, indolyl, benzimidazolyl, quinazolyi~ or quinozalyl radical, the aryl or heterocyclic radical optionally carrying 1 or 2 identical or diff'rent substituents selected from phenyl,, a2lky! with 1 to 8 carbon atoms, cyclo- alkyl. with 3 to 7 carbon atoms, alkenyl or alkinyl with in each case 2 to 6 carton atoms, alkoxy, Ukenoxy or alkinoxy with in each ca.e up to 14 -carbon atomrs, an alkylene chain with 3 to 6 carbon atoms, dioxyalkylene~ with 1 or 2 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, di- fluoromethoxy, tetrafluoroethoxy, nitro, cyano, azido, hydroxyl, amino, mono- or di-alkylamrino with in each case 1 to 14carbon atoms per alkyl group, carboxyl, carbalkoxy with 2 to 14carbon atoms, carboxamido, sulphonamido and sulphornylalkyl or

   Le A 20 638

   Le A Zu

   38 alkylmercapto with in -ach case 1 to 4 carbon atoms per alkyl radical; 1 i R and R are identical or different and each represent a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which has up tc 'i :carbon atoms and is optionally interrupted in the chain by 1 or 2 oxygen atoms and is optionally substituted by fluorine, chlorine, hydroxyl, phenyl, phenoxy, phenylthio or phenylsulphonyl, the phenyl radicals in turn optionally being substituted by 1 or 2 identical or different substituents selected from nitro, trifluoromethyl, cyano, fluorine, chlorine and alkyl and dialkylamino with in each case 1 to 4 carbon atoms in the alkyl radicals; 4 4 2 2' R2, R R and R are identical or different and each represent a hydrogen atom or a straight- chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which has up to 8 carbon atoms and is in tuzLn optionally substituted by fluorine, chlorine, hydroxyl, phenyl, amino, alkylamino or cycloalkyl with up to 6 carbon atoms; P 3 ad R3 are identical or different and each represa'nt a hydrogen atom or a straight-chain or branched alkyl radical which has up to 8 carbon atoms and optionally is interrupted in the chain by an oxygen atom or is substituted by hydroxyl or halogen, or represent optionally substituted phenyl, benzyl or phenethyl radical; Y and Y' are in each de identical or different and each denote -CO0-, -CONH-, -COS- or -SO 2 and X represents a bridge member which has at least one CH2 group which is not bonded to the rings and at most 9 adjacent CH2 as chain members, it

   Le A 20 638

   c I i i i I: 1

   Le A 20 638

   o

   being possible for( the bridge member additionally Q) contain, in any desired sequence, 1 to 4 identical or different chain members selected from 6 0, S, SO 2 CO, CS, NR 5 C(R 6 2 R6 C=C, CH=N, phenylene, naphthylene, pyridylene and cycloalkylene or cycloalkenylene with in each case 3 to 7 carbon atoms, piperazinylene, piperidinylene, pyrrolidinylene and morpholinylene, wherein R5 represents a hydrogen atom, a benzyl radical or an alkyl radical with 1 to 4 carbon atoms and R represents a hydrogen atom, a benzyl or phenyl radical, a fluorine or chlorine atom, an alkyl radical with 1 to 4 carbon atoms, a hydroxyl, tri- fluoromethyli cyano, carboxyl or amino radical, an alkylamino radical with 1 to 4 carbon atoms in the alkyl radical or a carbalkoxy radical with 1 to 4 carbon atoms in the alkoxy radical. 3. Compounds according to claim 2, in which R and R' are identical or different and each represent a phenyl radical or a thienyl, furyl, naphthyl, or pyridyl radical, the phenyl radical optionally being substituted by one or two identical or different substituet'-s selected from nitro, cyano, azido, halog,.1' trifluoromethyl, hydroxyl, amino and alkyl, alkoxy, alkylamino and alkyl- mercapto with in each case 1 or 2 carbon atoms in the alkyl groups, R 1 and R l are identical or different and each represent a straight-chain or branched hydrocarbon radical which has up to 6 carbon atoms and is optionally interrupted in the chain by an oxygen and is optionally substituted by fluorine, chlorine, hydroxyl, phenyl or phenoxy, R2 2, R and R are identical or different and

   Le A 20 638

   Le A 20 638 Le A 20 638

   40 ing to any o each represent a hydrogen atom or a straight-chain a) a hydrox or branched alkyl radical which has up to 4 carbon formula atoms and is optionally substituted by fluorine, chlorine, hydroxyl, phenyl or amino. R 3 and R 3 are identical or different and each represents a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms or a phenyl, benzyl or phenethyl radical which is optionally substituted by hydroxyl, fluorine or chlorine, 5 in which Y and Y' are in each case identical or different R, R and denote -COO-, -CONH-, -CO- or and iean X represents a bridge member which has at least reacted w one CH 2 group which is not bonded to the rings 3-carboxylic and at most 9 adjacent Cd 2 groups as chain members, it being possible for the bridge member additionally to contain, in any desired sequence, 1 to 3 identical or different chain members selected from 5 0, S, CO, CS, NR C(R 6 2 CH=N, phenylene, in which naphthylene, pyridylene, cycloalkylene with 5 to I 7 carbon atoms, piperazinylene, piperidinylene, meanj pyrrolidinylene and morpholinylene, a cai wherein 15 in an inert c R represents a hydrogen atom, a benzyl radical or binding agent an alkyl radical with 1 to 4 carbon atoms, and water being E 2R represents a hydrogen atom, a benzyl or phenyl b) a 1,4-dil radical, a fluorine or chlorine atom, or an alkyl formula radical with 1 to 4 carbon atoms or a hydroxyl, trifluoromethyl, cyano, carboxyl or amino radical. 4. Any one of the compounds according to claim 1 which are hereinbefore specifically mentioned, other than the compounds of Examples 21 to 31. Any one of the compounds according to claim 1, in which which are hereinbefore specifically mentioned in Examples R, R 1 21 to 31. claim 6. A process for the production of a compound accord- Le A 20 638 Le A 20 638

   Le A 20 638 Le A 20 63,8

   141 is reacted with a ing to any of claims 1 to 4, in which, formula a) a hydroxy-1,4-dihydropyridine derivative of the general formula in which R 5 X has the 1 (II) Z and Z' a SOOC Y-X-OH and repreE R wherein R 5 has thE in which 10 in a molar ratio c R, R1 R2 R3, R 4 Y and X have the same organic solvent at meanings as in claim 1, only'a compound o: reacted with an equivalent amount of a dihydropyridine- and do not rep: 3-carboxylic acid derivative of the general formula by this variant, c) an ylidene--

   HY' COOR1 (III) II 21 41 N RL F, F 1 and in which is reacted with a R R2 1 R3 1, FL and Y' have the same general formula meanings as in claim 1, but Y' does not represent a carbonyl group, in an inert organic solvent in the presence of water- in which binding agents at a temperature between OoC F3 F3 and 1800 C, water being split off, or as in cla b) a 1,4-dihydrop3 idinecarboxylic acid of the general in a molar ratio formula 25 organic solvent a 7. A procesE FL 1000 COOH reaction is carr: (IV) agent. 8. A procesv reaction is carr: in which in an alcohol. 1 RL2 3 and Ii, F FL R 4 have the same meanings as in 9. A proces claim 1,

   Le A 20 638 Le A 2o 638

   Le A 20 63.8

   42 42

   is reacted with a bifunctional compound of the general. formula Z-X-Z' (V) in which X has the same meaning as in claim 1 and Z and Z' are in each case.identical or different and represent a hydroxyl, mercapto or NHR 5 radical, wherein R5 has the same meaning as in claim 1, in a molar ratio of about 2:1 in the presence of an inert organic solvent at a temperature between 0 C and 1800C, only a compound of the general formula in which Y and Y' do not represent a carbonyl group being obtained by this variant, or c) an ylidene-3-keto ester of the general formula

   SCOR 2 R-CH=C (VI) 1 COOR

   R, R 1 and R 2 have the same meanings as in claim 1, is reacted with an enaminocarboxylic acid ester of the general formula R -C=CH-Y-C-Y'-CH=C-R (VII) 3' 1 '1 R NH HNR in which R) R 3 4 4 R R R Y and Y' have the same meanings as in claim 1, in a molar ratio of about 2:1 in the presence of an inert organic solvent at a temperature between OOC and 180 0 C. 7. A process according to Claims 6b), in which the reaction is carried out in the presence of a water-binding agent. 8. A process according to claim 6c),'in which the reaction is carried out in an aprotic organic solvent or in an alcohol. 9. A process according to any of claims 6a), 6b) and 7, r

   43 in which the reaction is carried out in an aprotic organic solvent. A process according to any of claims 6a), 6b), 6c) and 7 to 9, in which the reaction is carried out at a temp- erature between 200 and 120 0 C. 11. A process for the production of a compound according to claim 1, substantially as described in any one of Examples 1 to 12. A process for the production of a compound according to claim 1, substantially as described in any one of Examples a to 31. 13. A compound according to claim 1, whenever produced by the process of any of claims 6 to 11. 14. A compound according to claim i, whenever produced by the process of claim 12. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 4 and 13 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. 16. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 4 and 13 in the form of a sterile or physiologically isotonic aqueous solution. 17. A composition according to claim 15 or 16 contain- ing from 0.5 to 90% by weight of the said active ingredient. 18. A medicament in dosage unit form comprising a compound according to any one of claims 1 to 4 and 13. 19. A medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a compound according to any one of claims 1 to 4 and 13. A method of combating circulatory illnesses in human and non-human animals which comprises administering

   Le A 20 638 py r-ane- j-c arb oxy late]

   Le A 20 638

   44 to the animals an active compound according to any one of claims 1 to 4 and 13 either alone or in admixture with a diluent or in the form of a medicament according to claim 18 or 19. 21. A method according to claim 20 in which the active compound is administered intravenously in an amount of 0.01 to 10 mg per kg body weight per day. 22. A method according to claim 20 in which the active compound is administered orally in an amount of 0.05 to mg per kg body weight per day. 23. A pharmaceutical composition according to any of claims 15 to 17 in which the active ingredient is a com- pound according to claim 5 or 14. 24. A medicament according to claim 18 or 19 comprising a compound according to claim 5 or 14. A method according to any of claims 20 to 22 in which the active compound is a compound according to claim or 14 or the medicament is a medicament according to claim 24. 26. A compound of formula as defined in claim 1, for use in combating circulatory illnesses.

   27. A compound as described herein.

   DATED this 21st day of October 1981

   BAYER AKTIENGESELLSCHAFT

   By its Patent Attorneys

   ARTHUR S. CAVE CO.

   Le A 20 638

   I :r ii i